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Bouquet was born into a moderately wealthy family in Rolle, Swiss Confederacy, the oldest of seven brothers. The son of a Swiss roadhouse owner and his well-to-do wife, he entered military service at the age of 17.[1] Like many military officers of his day, Bouquet traveled between countries serving as a professional soldier. He began his military career in the army of the Dutch Republic and later was in the service of the Kingdom of Sardinia. In 1748, he was again in Dutch service as lieutenant colonel of the Swiss guards.

Bouquet ordered the construction of a new British garrison on the site of Fort Duquesne. Bouquet is given credit for naming the new garrison Fort Pitt and the village that quickly grew up around it Pittsburgh.

The Indians returning English captives to Colonel Henry Bouquet in November 1764.

In 1763, Pontiac's War began on the frontier. Pontiac, an Ottawa war leader, began urging the defeated Indian tribes that had been allied to the French during the French and Indian War to join together to continue the fight against the British. Pontiac initiated attacks on frontier forts and settlements, believing the defeated French would rally and come to their aid. The conflict began with the siege of Fort Detroit on 10 May 1763. Fort Sandusky, Fort Michilimackinac, Fort Presque Isle, and numerous other frontier outposts were quickly overrun.

Several frontier forts in the Ohio Country had fallen to the allied tribes, and Fort Pitt, Fort Ligionier, and Fort Bedford along Forbes's road were besieged or threatened. Bouquet, who was in Philadelphia, threw together a hastily organised force of 500 men, mostly Scots Highlanders, to relieve the forts. On 5 August 1763, Bouquet and the relief column were attacked by warriors from the Delaware, Mingo, Shawnee, and Wyandot tribes near a small outpost called Bushy Run, in what is now Westmoreland County, Pennsylvania. In a two day battle, Bouquet defeated the tribes and Fort Pitt was relieved. The battle marked a turning point in the war.

It was during Pontiac's War that Bouquet gained a certain lasting infamy. In a series of letters during the summer of 1763 between Bouquet and his commander, General Jeffery Amherst, the idea was raised of infecting the Indians who had besieged Fort Pitt with smallpox by giving them infected blankets from the fort's smallpox hospital. Amherst wrote to Bouquet, then in Lancaster, on about 29 June 1763: "Could it not be contrived to send the small pox among those disaffected tribes of Indians? We must on this occasion use every stratagem in our power to reduce them."[3] Bouquet agreed, replying to Amherst on 13 July: "I will try to inoculate the Indians by means of blankets that may fall in their hands, taking care however not to get the disease myself."[4] Amherst responded on 16 July: "You will do well to try to inoculate the Indians by means of blankets, as well as to try every other method that can serve to extirpate this execrable race."[5]

The journal of William Trent, the commander of the militia at the fort, has provided what some claim may be evidence that at least some measure of this plan was carried out is provided by though it appears that Trent had already carried out the plan before Amherst had proposed it to Bouquet. The claim that these letter provide evidence is disputed:

[June] 24th [1763] The Turtles Heart a principal Warrior of the Delawares and Mamaltee a Chief came within a small distance of the Fort Mr. McKee went out to them and they made a Speech letting us know that all our [POSTS] as Ligonier was destroyed, that great numbers of Indians [were coming and] that out of regard to us, they had prevailed on 6 Nations [not to] attack us but give us time to go down the Country and they desired we would set of immediately. The Commanding Officer thanked them, let them know that we had everything we wanted, that we could defend it against all the Indians in the Woods, that we had three large Armys marching to Chastise those Indians that had struck us, told them to take care of their Women and Children, but not to tell any other Natives, they said they would go and speak to their Chiefs and come and tell us what they said, they returned and said they would hold fast of the Chain of friendship. Out of our regard to them we gave them two Blankets and an Handkerchief out of the Small Pox Hospital. I hope it will have the desired effect. They then told us that Ligonier had been attacked, but that the Enemy were beat off.[6]

It is not clear if Amherst and Bouquet had knowledge of Trent's actions when they were discussing the idea or if Trent had been given orders to carry out the plan from Bouquet, Amherst, or someone else or if he came up with the idea on his own. What is know is than an outbreak of smallpox did occur among the area Indians prior to the incident but smallpox at Fort Pitt along with some outside infected areas generated even greater damage to the Native Americans. Since the smallpox incident at Fort Pitt, it is estimated that 400,000-500,000 (possibly up to 1.5 million) Native Americans - men, women, and children - died during and years after the Pontiac's War, mostly from smallpox given by the British and some in the outside infected areas than in combat. The incident at Fort Pitt was one of the known case of deliberate biological warfare in North America.[7][8][9]

By the autumn of 1764, Bouquet had become the commander of Fort Pitt. To subdue the ongoing Indian uprising, he led a force of nearly 1,500 militiamen and regular British soldiers from the fort into the Ohio Country.[10] On 13 October 1764, Bouquet's army reached the Tuscarawas River. Shortly thereafter, representatives from the Shawnees, Senecas, and Delawares came to Bouquet to sue for peace.

Bouquet then moved his army from the Tuscarawas River to the Muskingum River at modern-day Coshocton, Ohio. This placed him in the heart of tribal lands and would allow him to quickly strike the natives' villages if they refused to cooperate. As part of the peace treaty, Bouquet demanded the return of all white captives in exchange for a promise not to destroy the Indian villages or seize any of their land. The return of the captives caused much bitterness among the tribesmen, because many of them had been forcibly adopted into Indian families as small children, and living among the Native Americans had been the only life they remembered. Some 'white Indians' such as Rhoda Boyd managed to escape back into the native villages; many others were never exchanged. Bouquet was responsible for the return more than 200 white captives to the settlements back east.

In 1765, Bouquet was promoted to brigadier general and placed in command of all British forces in the southern colonies. He died in Pensacola, West Florida, on 2 September 1765, probably from yellow fever.

Bouquet is referred to in Conrad Richter's 1953 novel The Light in the Forest, which tells the story of one young man returned to his white family as part of the 1764 treaty. The Colonel is also referred to in Paul Muldoon's poem, "Meeting the British".